This proposal is designed to provide the Principal Investigator, Pamela A. Guerrerio, with the necessary knowledge, skills, and experience required to transition to a position as an independent researcher in the field of allergy and immunology. Dr. Guerrerio outlines a five-year plan to investigate the basic mechanism by which TGF- regulates immunity, and specifically how it participates in the pathogenesis of Th2-mediated disease. This work will be performed under the mentorship of Dr. Harry C Dietz, Victor McKusick Professor of Medicine and Genetics and an investigator in the Howard Hughes Medical Institute at Johns Hopkins University. Dr. Dietz has an impressive track record of mentoring young investigators for successful careers in academic medicine, including those funded under the K award mechanism. Dr. Guerrerio also has the support of a team of extraordinary physician scientists at Johns Hopkins including Dr. Jonathan Powell, Dr. Zhou Zhu, and Dr. Robert Wood. All of these individuals have committed their time, resources, and expertise to facilitate Dr. Guerrerio's career development and research goals. In addition, the candidate will acquire additional skills and training through didactic coursework at the highly regarded Johns Hopkins Bloomberg School of Public Health. The candidate's past academic experiences underscore her commitment to academic medicine and her desire to acquire rigorous and complete scientific training. She completed the NIH-sponsored Medical Scientist Training Program at Johns Hopkins University and did her graduate work under the mentorship of Dr. Dietz. During graduate school, she performed very basic research in the mechanisms of RNA stability, and discovered a novel mRNA decay pathway, termed nonstop decay, that appears to be a new mechanism to regulate gene expression. Using murine models, she also demonstrated how another RNA surveillance mechanism, nonsense mediated decay, is required for normal lymphocyte development and proper allelic exclusion. She completed both a residency in Pediatrics and a fellowship in Allergy and Immunology at Johns Hopkins University. During fellowship, she became interested in food allergy and mucosal tolerance and has led several studies to investigate the role of human dendritic cells and basophils in the pathogenesis of food allergy. Dr. Guerrerio joined the faculty at Johns Hopkins as an Assistant Professor in July 2009. Her research experiences have afforded her with a unique background in molecular biology, genetics, immunology, and both human and murine models of disease. She is now poised to apply these skills, under the guidance of her mentors, to study the basic immunologic mechanisms that lead to loss of tolerance and development of food allergy. The research in this proposal will focus on the role of TGF- in the development of allergic disease. The scientific approach will involve the study of Loeys-Dietz syndrome (LDS), a newly described autosomal dominant disorder caused by mutations in the TGF- receptors, as a model system. LDS appears to be the first Mendelian disorder associated with the development of food allergy and eosinophilic esophagitis, and offers an unparalleled opportunity to study the role of TGF- in the human immune system. Specific Aims include: I): Investigate the signaling alterations in human lymphocytes caused by LDS mutations and how they lead to increased Th2 effector responses II): Define the biochemical and cellular events leading to the increased propensity for Th2-mediated disease in LDS mice, and how this process can be mitigated by pharmacologic inhibition of TGF- signaling. The scientific training obtained through this grant will lead to publications, data, and experience that will enable the candidate to secure independent NIH funding within the next 3-4 years and establish herself an independent physician scientist. Food allergy and eosinophilic esophagitis have become increasingly common clinical problems for which there is no known cure. We have recently identified the TGF- pathway to be specifically involved in the development of these disorders. In this proposal, we will seek to understand the mechanism by which alterations in TGF- signaling predispose to allergic disease, and how these pathways might be manipulated for therapeutic benefit.